tbuckley/cabot-search huggingface dataset:
Presence of CD8<sup>+</sup> cytotoxic T-cells in proximity to tumor cells, TIM3, CTLA-4 and prognostic implications for muscle-invasive urothelial cancer.
Authors: Nicolaus F. Debatin, Henning Plage, Tobias Klatte, Sefer Elezkurtaj, Paul G. Bruch, Maria De Santis, David Horst, Andreas H. Marx, Margit Fisch, Marcin Slojewski, Krystian Kaczmarek, Thorsten Ecke, Steffen Hallmann, Stefan Koch, Nico Adamini, Maximilian Lennartz, Guido Sauter, Henrik Zecha, Thorsten Schlomm, Niclas C. Blessin
Journal: Journal of Clinical Oncology (2023)

4582 Background: Although it is well known that the quantity of specific immune cell types can provide prognostic information in bladder cancer, only little is known about the prognostic relevance of the localization of immune cells within the tumor microenvironment. Methods: To study the spatial interplay of different immune cell subpopulations and its prognostic role in bladder cancer, 2463 urothelial bladder carcinomas were immunostained with 21 antibodies (i.e., TIM-3, PD-L1, PD-1, CTLA4, CD3, CD8, CD4, FOXP3, CD20, CD68, CD163, CD11c, panCK, Ki67, CD31, Vimentin, HLA-DRa, Myosin-11, Desmoglein 3, PAX-8, and CDH16) using BLEACH&amp;STAIN multiplex fluorescence immunohistochemistry in a tissue microarray format and analyzed using a framework of neuronal networks for image analysis. Thus, Spatial immune parameters were compared with histopathological parameters and overall survival data. Results: The identification of more than 300 different immune cell subpopulations and the characterization of their spatial relationship resulted in numerous spatial interaction patterns. 32 immune parameters showed prognostic significance in univariate analyses of which 16 were independent from pT, pN, and histologic grade in muscle-invasive bladder cancer. The strongest association to clinical outcome was identified for intraepithelial CD8 + cytotoxic T-cells (AUC: 0.70) while stromal CD8 + cells were less relevant (AUC: 0.64, p=0.016). A favorable prognosis of inflamed cancers with high levels of “exhaustion markers” suggests that TIM3, PD-L1, PD-1, and CTLA-4 on inflammatory cells do not hinder anti-tumoral immune response in tumors rich of tumor infiltrating tumor cells. Conclusions: The density of intraepithelial CD8 + T-cells was the strongest prognostic feature in muscle-invasive bladder cancer. Given that tumor cell killing by CD8 + cytotoxic T-lymphocytes through direct cell-to-cell-contacts represents the “terminal end route” of anti-tumor immunity, the quantity of “tumor-cell adjacent CD8 + T-cells” may constitute a surrogate for the efficiency of cancer recognition by the immune system that can be measured straightaway using conventional brightfield IHC in routine pathology as the CD8 labelling index.
Costs and health care resource utilization (HCRU) for patients with advanced biliary tract (aBTC) cancer using administrative databases in Ontario, 2010 to 2020.
Authors: Soo Jin Seung, Hasnain Saherawala, Iqra A. Syed, Derek L. Clouthier, Cal S. Shephard, Eric Xueyu Chen
Journal: Journal of Clinical Oncology (2023)

e16112 Background: Gemcitabine and cisplatin (gemcis) has been the standard of care for biliary tract cancer (BTC) for over a decade. One US model predicted the total lifetime cost of gemcis per patient to be $54,077 in 2020 CAD, although not all costs were considered. Our study objectives included quantifying updated costs and health care resource utilization (HCRU) associated with advanced BTC using real-world, population-level data from Ontario databases. Methods: We conducted a retrospective population-level study of patients diagnosed with recurrent or unresectable/advanced BTC (gallbladder cancer [GBC], intrahepatic and extrahepatic cholangiocarcinoma [IHC and EHC], Ampulla of Vater [AoV]) between January 1, 2010 and December 31, 2019. Follow-up data were available until December 31, 2020. HCRU and costs were calculated from the start date of first line (1L) of BTC-specific systemic therapies to death or the end of March 31, 2020 whichever occurred first. A macro-based costing methodology (GETCOST) was used and the mean cost per patient was reported in 2020 Canadian dollars (CAD). Mean cost per patient was calculated from diagnosis till the end of follow-up or death. The total number of HCRU-specific encounters for all years was divided by the number of BTC patients who used that HRCU in order to report the mean number of HCRU encounters (e.g., cancer clinic visits and inpatient hospitalizations). Results: Of 2,142 advanced BTC patients identified, 1,968 were diagnosed with non-AoV cancers (GBC, IHC, EHC or general BTC not otherwise specified) and 174 patients were diagnosed with AoV cancer. The mean cost per patient for all 1L-treated patients was $36,662 ($36,378 for non-AoV compared to $40,092 for AoV patients). By 1L-specific therapies, the highest mean cost per patient was for patients on gemcitabine and taxane combinations (gemtaxane) at $44,190, followed by gemcitabine and cisplatin (gemcis) at $34,507, then FOLFOX or FOLFIRI (fol) at $39,002 and carboplatin and gemcitabine (gemcarb) at $30,905. Untreated patients had a mean cost per patient of $42,136. The mean number of cancer clinic visits per patient per year during 1L ranged from 9.7 (untreated) to 13.7 (gemcis), while the inpatient hospitalizations per patient per year during 1L ranged from and 1.5 (gemcarb, fol and gemtaxane) to 2.4 (untreated). Conclusions: This study reports Canadian-specific, real-world costs and HCRU results of over 2,000 BTC patients. While cost results were stratified by type of BTC (AOV and non-AOV) and type of 1L therapies, the mean cost per patient ranged from $30,905 CAD to $44,190 CAD and HCRU results indicated substantial mean number of cancer clinic visits and inpatient hospitalizations. Thus, BTC patients incur a significant economic burden to the patients and Ontario public payer health system.
Defining the prevalence of inherited DNA damage repair genetic variants (DDRv) in men with prostate cancer (PCa) detected by PSMA PET.
Authors: Edward Maldonado, Thomas A. Hope, Rahul Raj Aggarwal, Daniel H Kwon, Li Zhang, Kelly Gordon, Barry Tong, Adina Bailey, Vipul Kumar, Ivan de Kouchkovsky, Vadim S Koshkin, Hala Borno, Jonathan Chou, Rohit Bose, Lawrence Fong, Arpita Desai, Terence W. Friedlander, Eric Jay Small
Journal: Journal of Clinical Oncology (2023)

e17010 Background: Approximately 12% of patients (pts) with metastatic PCa (mPCa) identified by conventional imaging harbor DDRv. The increased use of PSMA PET has identified a group of pts with extra-prostatic PCa which is not apparent on conventional imaging and for whom the frequency of germline DDRv testing remains unknown. Methods: A single-institution retrospective analysis of patients with PCa detected by PSMA PET who had also undergone germline genetic testing was undertaken. Data collected included PSA level at time of PSMA PET imaging, stage/Gleason score at diagnosis (dx), rationale for germline testing, castration status, and whether the metastatic disease identified on PSMA PET represented de novo or recurrent mPCa. Germline sequencing results were evaluated for 16 DNA damage repair genes: ATM, ATR, BAP1, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, GEN1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51C, and RAD51D. The frequency of DDRv was evaluated in groups defined by PSMA imaging results: localized (N0M0), Node-Positive (N+M0), metastatic (M+) PCa. Results: Of 795 PCa pts who underwent germline testing and 2101 PCa pts who underwent PSMA PET imaging, 386 had undergone both, and constitute the study cohort. In the study cohort the distribution of PCa extent identified by PSMA PET was: 81/386 (21.0%) N0M0; 76/386 (19.7%) N+M0; 229/386 (59.3%) M+. There were no statistically significant differences in the prevalence of DDRv with regards to age, Gleason score at dx, PSA at time of imaging, castration status at time of imaging, rationale for germline testing, or if metastatic, whether de novo or recurrent. The distribution of DDRv is shown in the table. There were no statistically significant differences between groups. Conclusions: The overall frequency of pathogenic germline DDRv in PCa pts who had undergone PSMA PET imaging was 4.66%, considerably lower than what has been reported in men with mPCa detected with conventional imaging. The presence or absence of extra-prostatic PCa detected by PSMA PET imaging did not appear to affect the frequency of DDRv. Validation of these findings in other cohorts will be important to guide recommendations for germline genetic testing in the growing group of PCa pts undergoing PSMA PET imaging. [Table: see text]
RNA sequencing as a confirmatory assay and its impact on patient care in multiple cancer types.
Authors: Pashtoon Murtaza Kasi, Sofia Smirnova, Vladislav Nikulin, Jessica H. Brown, Nava Almog, Anna Ogloblina, Clinton Yam, Julio Antonio Peguero, Devesh Mahesh Pandya, Daniel Kerr, Nathan Fowler
Journal: Journal of Clinical Oncology (2023)

e15058 Background: Increasing evidence shows the ability of RNA sequencing (RNA-seq) to detect expression of multiple biomarkers with improved sensitivity and scalability, offering a more objective and reproducible interpretation of data compared to pathological assessment methods by immunohistochemistry (IHC). Further, ongoing research demonstrating strong correlation between RNA-seq gene expression values and IHC values suggests the utility of RNA-seq as an objective diagnostic approach. Here, we highlight 4 cases where discordance in expression levels measured by IHC and RNA-seq resulted in re-evaluation of IHC values and a subsequent change in the clinical course. Methods: All patients underwent RNA and DNA sequencing of tumor tissue as part of a standard-of-care workflow. Sequencing was performed and reported with the BostonGene Tumor Portrait test, utilizing whole-exome sequencing (WES) and transcriptome sequencing data for tumor analysis. Gene expression levels were evaluated by comparison to a reference cohort of patients with a similar diagnosis. Results: In one case, a 53-year-old female was diagnosed with metastatic cholangiocarcinoma. While IHC of her biopsy reported positive HER2 (+3) expression, RNA-seq revealed low expression. A repeated IHC assay confirmed negative HER2 expression, leading to a change in therapy options. Another 61-year-old female was diagnosed with triple negative breast cancer (TNBC) (IHC: ER 0%, PR 0%, HER2 1+). Integrated WES and RNA-seq analysis detected HER2 amplification (+8 copies), ERBB2-activating mutation, high ERBB2 (HER2) expression and a HER2-enriched PAM50 subtype. IHC was repeated, now showing positive HER2 (+3) expression. In order to target HER2, systemic treatment was changed to a combination containing trastuzumab and pertuzumab, resulting in pathological complete response. In the third case of an 85-year-old female with relapsed TNBC, IHC demonstrated 1% PDL-1 staining. In contrast, RNA-seq detected high PD-L1 expression leading the treating physician to repeat IHC. Staining showed high PDL-1 (CPS50), prompting a change in therapy to an anti-PDL-1 (pembrolizumab) therapy. Lastly, while IHC of a 21-year-old female diagnosed with diffuse large B-cell lymphoma (DLBCL) showed negative CD30, subsequent RNA-seq detected relatively high CD30 expression that prompted a second IHC evaluation confirming positive CD30 expression. Eventually, the diagnosis was changed to primary mediastinal B-cell lymphoma and DA-EPOCH was selected as the therapy. Conclusions: RNA-seq is emerging as an objective tool to evaluate key diagnostic and targetable events in multiple cancer types. The use of RNA-seq can also add value as an objective measurement to confirm critical IHC findings, potentially changing clinical care.
Impact of novel pan-RAS inhibitors on efficacy and resistance to AMG-510 and MRTX-1133 in pancreatic cancer cell lines.
Authors: Tariq Arshad, Howard Donninger, Becca von Baby, Rachel Ferrill, Joe Burlison, John Trent, Geoffrey J. Clark
Journal: Journal of Clinical Oncology (2023)

4155 Background: Mutant-activated RAS genes are the most frequently mutated gene family associated with cancer (almost 30% of all cancers contain a mutant RAS gene). KRAS is the predominant isoform mutated in cancer and is the isoform exclusively mutated in pancreatic ductal carcinoma (PDAC). Since almost all PDAC cases harbor a mutant RAS, it is arguably the most RAS-addicted tumor type. There is now considerable evidence implicating mutant KRAS as a driver of PDAC. Recently, several mutant KRAS-targeted therapies (sotorasib and adagrasib) have been developed and show promise in PDAC patients. We have developed a direct inhibitor of RAS with a predicted unique interaction region capable of directly binding to wild-type H- and K-RAS, but which shows preferential binding for KRAS G12D and G12C mutants. This novel inhibitor disrupts the RAS effector domain and blocks the ability of RAS to signal through its effectors. Methods: We used in silico virtual library screening to identify an initial candidate inhibitor which was effective at inhibiting the 3D growth of PDAC cells without affecting their growth in 2D. Subsequent iterative rounds of medicinal chemistry was then performed to identify a series of derivatives with enhanced activity, as determined by 3D growth inhibition assays and effects on Ras signaling, as determined by Western blot analysis of phosphor-ERK, phosphor-Akt and activation of Ral A. Results: Our series of RAS inhibitors effectively block PDAC cell growth in 3D without impacting their 2D proliferation and suppress the interaction of KRAS with its effector cRAF. The inhibitors also effectively inhibit RAS signaling in mutant RAS containing PDAC cells. Since our novel compounds are predicted to bind to RAS at a different site to either AMG-510 (G12C specific inhibitor) and MRTX-1133 (G12D specific inhibitor), we tested the co-operativity of our compounds with these existing agents. Our compounds enhanced the anti-proliferative effects of both MRTX-113 and AMG-510 in mutant KRAS G12D and G12C PDAC cells, respectively. Conclusions: We have developed a series of novel RAS inhibitors that directly bind preferentially to mutant KRAS that may serve as new mutant KRAS-targeted therapeutics, and that may also have the potential to enhance the efficacy or suppress the resistance of AMG-510 and MRTX-1133.
Association of positive ctDNA-based minimal residual disease assays during surveillance and undiagnosed concomitant radiographic recurrences in colorectal cancer (CRC): Results from the MD Anderson INTERCEPT program.
Authors: Arvind Dasari, Alisha Heather Bent, Kristin Alfaro-Munoz, Ryan W Huey, Benny Johnson, Michael Sangmin Lee, Maria Pia Morelli, Van K. Morris, Michael J. Overman, Christine Megerdichian Parseghian, Kanwal Pratap Singh Raghav, John Shen, Jason Willis, Timothy E. Newhook, Abhineet Uppal, Y. Nancy You, Tsuyoshi Konishi, George J. Chang, Scott Kopetz, Robert A. Wolff
Journal: Journal of Clinical Oncology (2023)

3522 Background: Observational cohorts have shown that detection of circulating tumor DNA (ctDNA)-defined minimal residual disease (MRD) following curative intent therapy has very high specificity and positive predictive value for future radiographic recurrence with a lead time of over 9 months. However, such data have not incorporated rigorous clinical evaluation for concomitant recurrence, nor have they established the clinical utility of MRD monitoring after completion of curative intent therapy. Methods: Pts with stages II-IV CRC (6/1/19 - 12/31/22, data cutoff) treated with curative intent at MD Anderson Cancer Center were evaluated with a tumor-informed MRD assay (Signatera, Natera), as part of the institutional INTERCEPT program that aims to integrate MRD-based testing into CRC clinical care. Surveillance visits including scans and tumor markers were performed per established guidelines. ctDNA was recommended post-operatively and q3m with each surveillance visit. Pts and providers were informed of the results and subsequent clinical courses including additional radiologic testing for ctDNA+ MRD tests were tracked. Results: 1259 pts were included in the INTERCEPT program (median 57y, [21-93]; 55% male; stage% I-III/IV 69/31; colon/rectum% 61/39), with 1049 pts tested after curative intent surgery. Of these, 159/1049 pts (15%) had ctDNA+; distribution of pts, % (+ve/total) from time of such surgery in m was: 0 - 3 (54.6/43.8); 3-6 (21.3/30); 6-12 (24/33.2). Of the pts with ctDNA+ after surgery, 49 pts (32%) were ctDNA+ prior to or during adjuvant therapy and 86 (57%) during surveillance. Of the 86 pts who were ctDNA+ during surveillance, imaging revealed concomitant new metastases in 46 (53%); i.e. only 40 (47%) were true MRD+. A total of 191 imaging studies were done (range 1-4) within 90d of the initial ctDNA+ including 99 as routine surveillance concurrent with ctDNA testing and 92 as additional follow up based on results. Of 40 pts with true MRD, majority (27 pts, 67.5%) were enrolled onto ongoing MRD trials ( https://crcmrd.com/ ). Conclusions: Our experience provides support for the feasibility of incorporation of MRD testing as part of routine surveillance. ctDNA+ results trigger a high rate of reflex imaging and, as a result, 53% of ctDNA+ patients have concomitant new radiographic findings. While clinical trials are feasible in true MRD+ pts, eligibility criteria for these trials need to be carefully specified about adequate radiographic evaluation.
Differences of RAS/BRAF mutations between ISCC and RSCC in a Chinese population.
Authors: Yuhong Chen, Yixian Qiu, Yanrui Zhang, Yun Zhang, Xiayuan Liang, Feng Lou, Shanbo Cao, Jiayue Qin
Journal: Journal of Clinical Oncology (2023)

e15636 Background: According to the location and different clinical manifestations, colon cancer can be divided into left-sided colon cancer (LSCC) and right-sided colon cancer (RSCC). There are significant differences in morphology, molecular biology, and drug sensitivity between these two type. In addition, colorectal cancer is associated with the mutation of many essential tumor suppressor genes, such as proto-oncogene (KRAS), serine/threonine protein kinase (BRAF), etc. At that point, this study retrospectively analyzed the RAS/BRAF mutation landscape and studied the gene expression differences between RAS/BRAF-mutant and wild-type patients respectively in LSCC and RSCC, to provide some reference for potential treatment plans. Methods: We retrospectively profiled the somatic mutations of 497 patients with colon cancer from the General Hospital of Southern Theatre Command and the TCGA database using 808-gene-panel target-capture next-generation sequencing. Tumor mutation burdens (TMB) were calculated using an Acornmed panel with 808 cancer-related genes. Results: Among 415 LSCC, 48.7% (n = 202) patients harbored RAS mutations, of which 183 carried KRAS mutations and 19 had NRAS mutations. Five main subtypes of KRAS mutation were detected including G12D (28.7%), G12V (17.5%), G13D (13.2%), A146T(8.5%), G12C (7.9%). 3% (11) of LSCC patients were found to have BRAF mutation, including BRAF V600E(63.6%), D594G(18.2%), G466E(9.1%), K601E(9.1%). We explored differentially expressed genes between RAS/BRAF-mutant and wild-type patients. The top5 mutant genes found only in LSCC RAS/BRAF-mutant cohort include JAK2(3%), TERT(2%), MSH6(2%), KMT2A(1%), NOTCH1(1%). In contrast, genes found only in LSCC patients with RAS/BRAF wild type include LATS2(2%), SMARCA4(2%), CBL(1%), SLX4(1%), CDKN2A(1%). Among 82 RSCC, 50% (41) patients harbored RAS mutations, of which 39 carried KRAS mutations and 2 carried NRAS mutations. 9% (39) of RSCC patients were found BRAF mutation, and the BRAF V600E was the only subtype found in the RSCC. In terms of differentially expressed genes, the top5 mutant genes found only in RAS/BRAF-mutant RSCC include NSD1(6%), ASXL2(4%), BARD1(4%), PPP2R1A(4%), SPRED1(4%), while genes found only in RAS/BRAF wild-type RSCC include ERBB2(17.6%), DICER1(11.8%), EP300(11.8%), ARID2(9%), BRIP1(9%).The TMB of RAS/BRAF wild-type RSCC patients was 33.2 mut/Mb, significantly higher than that of RAS/BRAF wild-type LSCC patients (7.0 mut/Mb, P = 0.01). Conclusions: RAS mutation and subtype were almost the same in LSCC and RSCC cohorts. BRAF mutation mainly occurred in RSCC, and the mutation subtype in RSCC was found only V600E, but we found three other BRAF subtypes D594G, G466E, and K601E in the LSCC cohort. Considering the differential expression genes in RAS/BRAF-mutant and wild-type cohorts in RSCC and LSCC patients, there may be more options for genetic targets in the future for LSCC and RSCC treatment.
Long-term quality of life and nutritional results of stomach-preserving surgery after sentinel node evaluation in patients with early gastric cancer: A multicenter, randomized phase 3 trial (SENORITA).
Authors: Bang Wool Eom, Hong Man Yoon, Young-Woo Kim, Jae Seok Min, Ji Yeong An, Hoon Hur, Young Joon Lee, Gyu Seok Cho, Young-Kyu Park, Mi Ran Jung, Ji-Ho Park, Woo Jin Hyung, Sang-Ho Jeong, Myeong-Cherl Kook, Mira Han, Byung-Ho Nam, Keun Won Ryu
Journal: Journal of Clinical Oncology (2023)

4070 Background: In the SENORITA trial, laparoscopic sentinel node navigation surgery (LSNNS) showed no significant difference in overall and disease specific survivals compared with laparoscopic standard gastrectomy (LSG). Here, we present the effect of stomach preservation surgery on QoL and nutritional outcomes, and identify risk factors affecting QoL in stomach preservation surgery. Methods: SENORITA was a prospective multicenter randomized trial. Patients diagnosed with early gastric cancer of 3 cm or less were randomly allocated (1:1) to LSNNS or LSG. The primary endpoint was 3-year disease-free survival. This analysis focuses on long-term quality of life and nutritional outcomes of patients who finally underwent stomach-preservation surgery in the LSNNS group. QoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and stomach module (STO22) at 3, 12, 24, and 36 months after surgery. Linear mixed model analyses were used to evaluate differences between treatment groups. This trial is registered with ClinicalTrials.gov, NCT01804998. Results: From March 2013 to March 2017, a total of 580 patients were randomly assigned in the SENROTA trial. Among them, 258 patients underwent sentinel node navigation surgery and 198 finally underwent stomach preservation surgery. QoL data was available in 194 patients and compared with those of 257 patients who underwent standard gastrectomy. The stomach-preservation group had better QoL in physical function, dyspnea, and appetite loss of C30 and dysphagia, pain, reflux symptoms, eating restriction, anxiety, taste change, body image, and total score of STO22. Regarding nutritional outcomes, body mass index, hemoglobin, protein, and albumin levels were significantly higher in the stomach-preservation group than in the gastrectomy group. In multivariate analyses, tumor location (greater curvature) was an independent favorable factor affecting global health status, reflux symptoms, eating restriction, and total score of STO22 at 3 months in the stomach-preservation group. Segmental resection was a risk factor for diarrhea and eating restriction at postoperative 3 year. Conclusions: The stomach-preservation surgery had better long-term QoL and nutritional outcomes compared with standard gastrectomy. These findings can help decision making about treatment for patients with early gastric cancer, especially or elderly or nutritionally high risk patients. Clinical trial information: NCT01804998 .